What were the management strategies for atherosclerotic coronary disease in the pre‑statin era?

Pre-Statin Era Management of Atherosclerotic Coronary Disease

The pre-statin era management of atherosclerotic coronary disease relied primarily on bile acid sequestrants, lifestyle modifications, and symptomatic treatment, with significantly less effective outcomes compared to modern statin-based therapy.

Primary Lipid-Lowering Agents

Bile acid sequestrants (cholestyramine and colestipol) were the cornerstone pharmacologic therapy for lowering cholesterol before statins became available. 1, 2

Cholestyramine (Bile Acid Sequestrant)

• The LRC-CPPT trial demonstrated that cholestyramine reduced the combined rate of coronary heart disease death plus non-fatal myocardial infarction by 19% over seven years in middle-aged men with severe hypercholesterolemia (total cholesterol >265 mg/dL, LDL-C >175 mg/dL). 2
• Cholestyramine achieved mean reductions in total cholesterol and LDL-C that exceeded diet and placebo by 7.2% and 10.4%, respectively. 2
• In the NHLBI Type II Coronary Intervention Trial, cholestyramine monotherapy slowed progression of coronary artery disease, with only 32% showing progression compared to 49% on placebo over five years. 2
• The St. Thomas Atherosclerosis Regression Study (STARS) showed that diet plus cholestyramine resulted in disease progression in only 12% of patients compared to 46% with usual care, and promoted modest regression of atherosclerotic lesions (mean absolute width increase of 0.103 mm). 2

Colestipol (Bile Acid Sequestrant)

• Colestipol worked through the same mechanism as cholestyramine, increasing clearance of cholesterol-rich low-density lipoproteins from plasma. 1
• The cholesterol-lowering effect was typically evident within one month, and levels returned to baseline within one month of discontinuation. 1
• Colestipol significantly increased lipoprotein LpAI, a particle within the HDL density range that promotes cholesterol efflux from cells, suggesting an antiatherogenic effect beyond simple cholesterol lowering. 1

Combination Therapy Strategies

In patients with heterozygous familial hypercholesterolemia who failed to respond adequately to bile acid sequestrants alone, combination therapy with nicotinic acid was the standard approach. 1

• The combination of colestipol and nicotinic acid further lowered serum cholesterol, triglycerides, and LDL-C while simultaneously increasing HDL-C values. 1
• In many patients with severe hypercholesterolemia, it was possible to normalize serum lipid values using this combination. 1
• Randomized controlled trials using diet plus colestipol with either nicotinic acid or lovastatin (early statin) for 2-4 years significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions compared to conventional measures. 1, 2

Acute Coronary Syndrome Management

ACE Inhibitors

• ACE inhibitor therapy improved survival rates in patients with acute myocardial infarction when started early after initial hospitalization, with the most pronounced benefits in patients with anterior infarction, pulmonary congestion, or reduced left ventricular ejection fraction. 3
• Evidence from large clinical trials documented consistent improvement in mortality when oral ACE inhibitors were administered in the hospital setting to patients with AMI, with or without early reperfusion therapy. 3
• ACE inhibitors were not administered in the presence of hypotension due to increased risk of adverse effects. 3
• Several trials showed reduction in heart failure rates and mortality in patients treated soon after fibrinolysis. 3

Glucose-Insulin-Potassium (GIK)

• GIK therapy was formerly thought to reduce mortality during AMI through several mechanisms, but recent clinical trials found no benefit in STEMI, making this a Class IIb, Level of Evidence C recommendation. 3

Critical Limitations of Pre-Statin Era

The pre-statin era had substantially inferior outcomes compared to modern statin therapy, with bile acid sequestrants achieving only modest cholesterol reductions and requiring high doses with significant gastrointestinal side effects. 1, 2

• Bile acid sequestrants typically achieved only 7-10% additional LDL-C reduction beyond diet alone, compared to the 30-50% reductions achievable with statins. 2
• The LRC-CPPT trial's 19% reduction in cardiovascular events with cholestyramine was achieved only in highly selected middle-aged men with severe hypercholesterolemia, and it remains unclear how these findings extrapolate to other populations including women. 2
• Serum triglyceride levels could increase or remain unchanged with bile acid sequestrant treatment, a significant limitation compared to statins. 1

Common Pitfalls in Pre-Statin Era Management

• Discontinuation of bile acid sequestrants resulted in rapid return of cholesterol levels to baseline within one month, requiring continuous therapy for sustained benefit. 1
• The combination of bile acid sequestrants with nicotinic acid, while more effective, carried increased risk of side effects and required careful monitoring. 1
• Early intervention strategies like prehospital or emergency department initiation of ACE inhibitors lacked sufficient evidence, with benefits only clearly demonstrated when started during hospitalization. 3